RESUMO
Varicose veins of lower extremities are a heritable common disorder. Mechanisms underlying its pathogenesis are still vague. Structural failures such as valve weakness and wall dilatation in saphenous vein result in venous retrograde flow in lower extremities of body. Reflux of blood leads to distal high venous pressure resulting in distended veins. In an earlier study, we observed a positive association between c.-512C>T FoxC2 gene polymorphism and upregulated FoxC2 expression in varicose vein specimens. FoxC2 overexpression in vitro in venous endothelial cells resulted in the elevated mRNA expression of arterial endothelial markers such as Delta-like ligand 4 (Dll4) and Hairy/enhancer-of-split related with YRPW motif protein 2 (Hey2). We hypothesized that an altered FoxC2-Dll4 signaling underlies saphenous vein wall remodeling in patients with varicose veins. Saphenous veins specimens were collected from 22 patients with varicose veins and 20 control subjects who underwent coronary artery bypass grafting. Tissues were processed for paraffin embedding and sections were immunostained for Dll4, Hey2, EphrinB2, α-SMA, Vimentin, and CD31 antigens and examined under microscope. These observations were confirmed by quantitative real-time PCR and western blot analysis. An examination of varicose vein tissue specimens by immunohistochemistry indicated an elevated expression of Notch pathway components, such as Dll4, Hey2, and EphrinB2, and smooth muscle markers, which was further confirmed by gene and protein expression analyses. We conclude that the molecular alterations in Dll4-Hey2 signaling are associated with smooth muscle cell hypertrophy and hyperplasia in varicose veins. Our observations substantiate a significant role for altered FoxC2-Dll4 signaling in structural alterations of saphenous veins in patients with varicose veins.
Assuntos
Fatores de Transcrição Forkhead/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Proteínas de Membrana/genética , Varizes/genética , Remodelação Vascular/genética , Actinas/genética , Actinas/metabolismo , Adulto , Idoso , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Western Blotting , Efrina-B2/genética , Efrina-B2/metabolismo , Feminino , Fatores de Transcrição Forkhead/metabolismo , Humanos , Imuno-Histoquímica , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Masculino , Proteínas de Membrana/metabolismo , Pessoa de Meia-Idade , Músculo Liso/metabolismo , Neovascularização Patológica/genética , Neovascularização Patológica/metabolismo , Molécula-1 de Adesão Celular Endotelial a Plaquetas/genética , Molécula-1 de Adesão Celular Endotelial a Plaquetas/metabolismo , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Veia Safena/metabolismo , Veia Safena/patologia , Veia Safena/fisiopatologia , Transdução de Sinais/genética , Regulação para Cima/genética , Varizes/metabolismo , Adulto JovemRESUMO
We evaluated the cardioprotective effect of Amalaki Rasayana (AR), a rejuvenating Ayurvedic drug prepared from Phyllanthus emblica fruits in the reversal of remodeling changes in pressure overload left ventricular cardiac hypertrophy (LVH) and age-associated cardiac dysfunction in male Wistar rats. Six groups (aging groups) of 3 months old animals were given either AR or ghee and honey (GH) orally; seventh group was untreated. Ascending aorta was constricted using titanium clips in 3 months old rats (N = 24; AC groups) and after 6 months, AR or GH was given for further 12 months to two groups; one group was untreated. Histology, gene and protein expression analysis were done in heart tissues. Chemical composition of AR was analyzed by HPLC, HPTLC and LC-MS. AR intake improved (P < 0.05) cardiac function in aging rats and decreased LVH (P < 0.05) in AC rats as well as increased (P < 0.05) fatigue time in treadmill exercise in both groups. In heart tissues of AR administered rats of both the groups, SERCA2, CaM, Myh11, antioxidant, autophagy, oxidative phosphorylation and TCA cycle proteins were up regulated. ADRB1/2 and pCREB expression were increased; pAMPK, NF-kB were decreased. AR has thus a beneficial effect on myocardial energetics, muscle contractile function and exercise tolerance capacity.
Assuntos
Cardiomegalia/tratamento farmacológico , Cardiomegalia/fisiopatologia , Medicina Tradicional , Mitocôndrias Cardíacas/metabolismo , Contração Miocárdica , Extratos Vegetais/uso terapêutico , Envelhecimento/metabolismo , Animais , Aorta/patologia , Aorta/fisiopatologia , Cardiomegalia/genética , Morte Celular/efeitos dos fármacos , Constrição Patológica , Metabolismo Energético/efeitos dos fármacos , Fibrose , Regulação da Expressão Gênica/efeitos dos fármacos , Masculino , Mitocôndrias Cardíacas/efeitos dos fármacos , Modelos Biológicos , Contração Miocárdica/efeitos dos fármacos , Extratos Vegetais/farmacologia , Pressão , Ratos WistarRESUMO
Endocardial endothelial cells (EECs), when compared with endothelial cells of arteries and veins, possess higher resistance to apoptosis-inducing anticancer agents. The mechanism of this resistance property is unknown. We have investigated the molecular mechanism, which contributes to increased cell survival capacity in EECs. We explored whether the resistance to apoptosis is associated with the cellular expression of ATP-binding cassette transporters such as P-glycoprotein, MRP-1, and ABCG2. We used primary and immortalized porcine endocardial endothelial cells (PEECs and hTERT PEECs) and compared the results with that in porcine aortic endothelial cells (PAECs), left atrioventricular valve endothelial cells (PVECs), and human umbilical vein endothelial cell line (EA.hy926). FACS and immunoblot analysis revealed a significantly higher expression of ABCG2 in PEECs and hTERT PEECs compared to PAECs, PVECs, and EA.hy926. Using apoptosis-inducing anticancer agents such as doxorubicin and camptothecin, through chromatin condensation assay and immunoblot analysis, we demonstrated a higher resistance to apoptosis in EECs compared to PAECs, PVECs, and EA.hy926. Interestingly, resistance in EECs reversed in presence of ABCG2 specific inhibitor, fumitremorgin C. Our observations suggest that an inherently high expression of ABCG2 in EECs protects them against apoptosis in presence of anticancer agents.
Assuntos
Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Antineoplásicos/toxicidade , Apoptose/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos , Células Endoteliais/efeitos dos fármacos , Proteínas de Neoplasias/metabolismo , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/antagonistas & inibidores , Animais , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Endocárdio , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Células Endoteliais da Veia Umbilical Humana/patologia , Humanos , Indóis/farmacologia , Proteínas de Neoplasias/antagonistas & inibidores , Suínos , Regulação para CimaRESUMO
Effective delivery of drugs to alveoli in a controlled manner using hydrophobic polymers as carriers has already been reported. Preclinical studies revealed that toxicity and hydrophobicity are related to each other in pulmonary delivery. Here, we are reporting a chemically modified dextran having amphiphilicity and cationicity achieved by controlled grafting of stearyl amine. Two proportions of lipopolymers were synthesized and physico-chemical characterization was carried out. In vivo evaluation of sub-acute toxicity of the synthesized lipopolymer in Sprague-Dawley rats was carried out for three months. This was followed by a histological evaluation of the sacrificed animal's lung. Further, the synthesized lipopolymer was formulated with drug (Rifampicin) loaded inhalable microparticles through spray drying. The final drug formulation was tested for toxicity and proinflammatory responses in human cell lines. Dose deposition efficiency of the formulation was determined using Anderson Cascade Impactor.
Assuntos
Dextranos/química , Dextranos/toxicidade , Inaladores de Pó Seco , Excipientes/química , Nanocápsulas/química , Rifampina/administração & dosagem , Administração por Inalação , Animais , Antibióticos Antituberculose/administração & dosagem , Cátions , Dessecação , Dextranos/administração & dosagem , Difusão , Composição de Medicamentos , Micelas , Nanocápsulas/toxicidade , Pós , Ratos , Ratos Sprague-Dawley , Tensoativos/química , Tensoativos/toxicidadeRESUMO
Terminalia bellerica has been used as a traditional medicine in a variety of ailments including anaemia, asthma, cancer, inflammation, rheumatism and hypertension. In this study, the free radical scavenging and antioxidant activities of methanol extract (ME) and its different solvent fractions (namely hexane (HE), ethyl acetate (EA), butanol (BL) and water (WA)) of the T. bellerica fruit pericarp were evaluated and compared with standard antioxidant compounds like gallic acid (GA), catechin and ascorbic acid. Among the different fractions tested, the EA fraction exhibited higher antioxidant and radical scavenging activity against 1,1-diphenyl-2-picrylhydrazyl (DPPH), superoxide and hydroxyl radicals than the other fractions, which may be attributed to its higher phenolic and flavonoid content, since a linear relation was observed between the phenolic content and the antioxidant parameters. The HPTLC analysis of the EA fraction revealed that it mainly contains GA and ferulic acid (FA) as major phenolics, and the higher antioxidant activities of EA fraction may be due to the presence of these compounds.